Melatonin is the principal hormone secreted by the pineal gland in all vertebrates. In all mammals studied to date, including humans, a nocturnal rise in the production of melatonin by the pineal gland is evident, regardless of whether the mammals are nocturnal or diurnal, and conversely, melatonin production by the body is acutely suppressed by light. Melatonin is involved in the coordination of photoperiod and physiological processes, e.g. in animals which use changes in the photoperiod to time their thermoregulation and reproduction, temporal signals to the thermoregulatory and reproductive systems are controlled by the daily rhythm in the duration of melatonin during the dark phase. Numerous studies have shown that melatonin has a potent influence on gonadal activity.
The timing of melatonin administration has been shown to be crucial for its biological activities. E.g., while in the case of rats whose circadian rhythms are disrupted or arrhythmic in constant light, as well as in the case of rats free running in constant darkness, their rhythms are synchronized by daily melatonin injections, by contrast it has been found that continuous availability of melatonin in circulation, or injection of melatonin in the morning, sometimes prevents gonodal responses to melatonin in the afternoon. The inventor has shown, e.g. in Zisapel et al, Neuroendocrinology 40: 102 (1985), that the inhibition by melatonin of the stimulated release of dopamine from rat hypothalamus, was highest in the early photophase and lowest in the early afternoon.
The ability of the animals or humans to respond to the melatonin signal may depend upon melatonin receptors. Thus, it has been shown that in rats and Syrian hamsters, under a daily schedule of 14 hours light/10 hours darkness, the densities of melatonin binding sites in discrete brain areas (hypothalamus, medulla-pons and hippocampus) vary significantly over the 24-hour period with different patterns and phases, but no such variation was observed in other brain areas (striatum, parietal cortex, cerebellum). Only a partial overlap existed between the timing of peaks or troughs of melatonin binding sites and crests or nadirs in tissue melatonin content, so that the rhythms in melatonin binding sites may not be due to autoregulation of the receptors by the endogenous hormone. In this connection, it has also been shown that injection of exogenous melatonin to young rats or hamsters in the morning or late afternoon did not affect the density or diurnal variations in melatonin binding sites in most brain areas; in the hippocampus and midbrain, melatonin injected in the morning prevented the usual late afternoon rise in melatonin binding sites, whereas melatonin injected in the late afternoon suppressed the nocturnal rise in melatonin binding sites in the midbrain only.
It is also known that exogenously administered melatonin when administered in the late afternoon elicits antigonadal responses and decreases serum concentrations of testosterone in hamsters and immature rats, whereas in pinealectomized hamsters held in long days, the duration of melatonin administration is crucial in that 10 h infusions in long days elicit gonadal regression in hamsters while after previous exposures to short days, 4-6 hour infusions of melatonin stimulated the gonads.
It is further known that in several species, including rats and humans, night-time melatonin production in the pineal gland declines with age. Moreover, a decline in 24 hour mean values and loss of circadian variations in melatonin binding sites was found to occur in discrete areas of the aged rat brain, as indicated by use of .sup.125 I-melatonin as a probe (Laudon et al, Neuroendocrinology, 48; 577, 1988). While the melatonin rhythm might not be the cause for the .sup.125 I-melatonin binding rhythms recorded in the rat brain, the possibility exists that the decline in amplitude of the melatonin rhythm leads to the dispersal of phase, resulting in the obliteration of rhythmicity in melatonin binding sites in the brain. In other words, the age-related decrease in melatonin levels and binding site density may lead to a decline in the ability of the neuroendocrine system to respond to photoperiodic messages.
Melatonin has been given to human subjects intravenously or orally and no significant toxicity has been observed. Various studies have demonstrated a melatonin-mediated fatigue and sometimes depression or sleep. Melatonin may not be hypnotic but it alters the timing of the sleep-wake cycles through its effects on circadian organization, e.g., recent studies have indicated that timing of the nocturnal sleep gate is temporarily related to the nocturnal increase in melatonin excretion, The "opening" of the sleepiness gate may represent a critical accumulation of melatonin which activates somogenic structures in the brain.
The use of melatonin for various therapeutic purposes has been the subject of a number of patents and patent applications. Thus e.g., U.S. Pat. No. 4,600,723 discloses the administration of melatonin in order to alleviate or prevent the negative effects of disturbances in circadian rhythms of bodily performance and function, such as may occur in a change of work patterns from day to night shift, or in cases of jet lag.
Moreover, U.S. Pat. No. 4,654,361 discloses the administration of melatonin order to lower intraocular pressure in a human, where such pressure is abnormally high, while U.S. Pat. No. 4,945,103 discloses a method of treating premenstrual syndrome by administering melatonin at dosage levels sufficient to alleviate the symptoms.
PCT Patent Application No. WO 87/004032 describes compositions, for treating or preventing psoriasis, which contain melatonin or related compounds. PCT Patent Application No. WO 88/07370 discloses the administration of melatonin for the purpose of inhibiting ovulation in human females, thereby effecting contraception, as well as for preventing breast cancer in women. The use of melatonin or related compounds is disclosed in PCT Patent Application No. WO 89/04659, as a component in pharmaceutical compositions in order to counteract the effects of aging. European Patent Application No. 0330625A2 discloses the production of melatonin and analogs thereof, for various therapeutic purposes, including the administration of melatonin in combination with an azidothymidine for the treatment of AIDS.
My prior U.S. patent application Ser. No. 07/697,714, filed May 9, 1991, relates to a method for correcting a melatonin deficiency or distortion in the plasma melatonin level and profile in a human subject, and to a pharmaceutical controlled-release formulation, which contains melatonin.
The entire contents of U.S. Pat. Nos. 4,600,723, 4,654,361, 4,945,103, PCT Patent Application No. WO 87/00432 PCT Patent Application No. WO 88/07370, PCT Patent Application No. WO 89/04659 and European Patent Application No. 0330625A2, and of my said prior U.S. Patent Application, are explicitly incorporated herein by reference.
The Prostate, Androgens and Melatonin
Although it is known that the volume of the seminal plasma is produced by the prostate, the seminal vesicles and the bulbourethral (Cowper's) glands, the specific biological function of the prostate gland is still unknown. Diseases caused by pathology of the prostate are some of the most common and devastating diseases in the human male. Abnormal overgrowth (hyperplasia) of the human prostate (BPH) occurs in over 80% of the male population before the age of 80 and 25% will require surgery at some time in order to alleviate urinary obstruction caused by this overgrowth (for review, see Oesterling, J. E., J. Andrology 12, 348-55, December 1991). The exact cause of BPH is not well defined, but is thought to occur as a result of epithelial-stromal interactions in the appropriate hormonal milieu, specifically, in the presence of androgens. Although prostatectomy is the current treatment of choice for BPH, medical therapies aimed at shrinking the enlarged gland are being developed as additional options.
Both the differentiation of the prostate gland and subsequent postnatal growth of the tissue are controlled by androgenic hormones synthesized in the testes, which are converted into dihydrotestosterone within the gland. Unregulated dihydrotestosterone action is believed to cause hyperplastic prostate growth. Androgen withdrawal has been shown to lead to programmed cell death (apoptosis) in the rat ventral prostate.
Testosterone deficiency leads to a rapid involution of the prostate, because androgen ablation inhibits the proliferation of the androgen-dependent prostatic glandular cells and induces these cells to undergo both cellular atrophy (i.e. decrease in cell height and secretory functions) and activation of a cascade of biochemical events, resulting in the energy-dependant programmed death of these cells. Thus, there are at least three cellular responses that androgens affect within the androgen-dependent prostatic glandular cells: secretion, proliferation and inhibition of death. The specific androgen moieties responsible for each of these responses within the prostate are not totally resolved. Quantitatively, the major circulating androgen in the blood is testosterone. Within the prostate, testosterone is rapidly converted to a series of metabolites, a major one being 5.alpha.-dihydrotestosterone (DHT). which is the active intracellular androgen in androgen-dependent prostatic glandular cells. It is known that Androgen metabolizing enzymes in the human BPH change t o a lower 3.alpha. hydroxysteroid reductase and a higher 3 ketosteroid 5.alpha. reductase when compared to normal tissue.
Recently developed methods for the treatment of BPH include e.g. chemical castration with luteinizing hormone-releasing hormone (LHRH) analogs resulting in androgen deprivation, but have the disadvantages of causing loss of testosterone-dependent functions such as muscle mass, libido and erection.
It is known that 50.alpha. reductase activity is elevated in prostatic stromal cells in BPH, and that treatment with 5.alpha. reductase inhibitors, decreases the size of the prostate in animals and humans suffering from BPH. Unlike castration, which reduces all androgens in the prostate, treatment with 5.alpha. reductase inhibitors lowers levels of DHT and its metabolites while increasing testosterone within the prostate. This large increase in prostatic testosterone could overcome some portion of the initial inhibition by the competitive 5.alpha. reductase inhibitors leading to incomplete inhibition of prostatal growth. In this respect it is noteworthy that melatonin does not increase circulating testosterone levels in humans. The mode of action of melatonin on prostatal development and growth may differ from that of 5.alpha. reductase inhibitors. Melatonin has been shown to stimulate 3.alpha. reductase activity but did not affect 5.alpha. reductase activity in BPH tissue samples (Horst and Adam, Horm. metab. Res. 14, 54, 1982) suggesting that melatonin could lower prostatic DHT levels by enhancing its conversion to 3.alpha. androstandiol.
Other methods, such as the use of non-steroidal antiandrogens which block testosterone mediated responses without suppressing testosterone levels, are still at the experimental stage.
Melatonin plays a major role in the control of reproductive physiology (reviewed by Tamarkin et al. Science 227, 714-720, 1985) especially in seasonal breeders, such as hamsters and sheep, in which it mediates the effects of short photoperiod on gonadal physiology. Certain parts of the brain, especially the hypothalamus, have been implicated as the sites of melatonin's antigonadal and neuroendocrine activities (Glass, Pin. Res. Rev. 6, 219-259, 1988). In the male rat, castration, or degeneration of the testicular Leidig cells, produced a marked decrease in melatonin binding sites particularly in the hypothalamus and hippocampus; this effect was reversed by injection of exogenous testosterone (Zisapel and Anis, Mol. Cell. Endocrinol. 60, 119-126, 1988). In the Syrian hamster, castration also led to a testosterone-reversible decrease in melatonin binding sites in the brain; this response was evident in animals maintained in short but not long days (Anis and Zisapel, Molec. Cell. Endocrinol. 76, 23-34, 1991.
It is further known that melatonin inhibits testicular testosterone synthesis in the rat (Peat and Kinson, Steroids 17, 251-264, 1971), decreases androgen synthesis in both testicular interstitial cells and tubules (Ellis, Endocrinology 90, 17-28, 1972), stimulates delta-4-reductase activity in the rat liver and hypothalamus (Frehn et al. J. Endocrinol. 60, 507-515, 1974), increases 5.alpha.-reductase of seminiferous tubules for both progesterone and testosterone (Ellis, Endocrinology 90, 17-28, 1972), increases adrenal secretion of reduced steroid metabolites in female rats (Ogle and Kitay, Neuroendocrinology 23, 113-120, 1977), and reduces accessory sex gland size in pinealectomized male rats kept in constant darkness without inhibiting testosterone metabolism (Shirama et al. J. Endocrinology 95, 87-94, 1982). Orally administered melatonin lowered ventral prostate and seminal vesicle weight and increase the 3.beta.-hydroxysteroid reductase but not 5.alpha. reductase in the ventral prostate and seminal vesicles of pinealectomized rats (Horst et al. Experimentia 388, 968-970, 1982). The effects of melatonin on prostatic androgen receptors depends on the age of the animal and light cycle exposure (Moeller et al. Res. Exp. Med. 183, 157-165, 1983). Melatonin in vitro augments the luteinizing hormone or chorionic gonadotrophin induced increase in secretion of estrogen and progesterone from rat granulosa cells (Fiske et al. Endocrinology 114, 407-410, 1984), and stimulates the secretion of progesterone by human and bovine granulosa cells in vitro (Webley and Luck, J. Reprod. Fert. 78, 711-717, 1986; Webley et al. J. Reprod. Fert 84, 669-677, 1988).
It has been shown that subcutaneous administration of high doses (750 mcg.) of melatonin enhances regression of the ventral prostate gland in presence of exogenous testosterone in castrated rats (Debeljuk et al, Endocrinology 87, 1358-1360, 1970) and decreases the weight of both the testes and the ventral prostate gland in hypophysectomized animals (Debeljuk et al, Endocrinology 89, 1117-1119, 1971). (It may be noted in passing that the amount of melatonin equivalent to that administered to rats by Debeljuk et al, for administration to an 80 kg human, would be more than 200 mg.) Other studies have shown that oral administration of 16-40 mcg. per day delayed pubertal development of male and female rats, including prostate development in the males (Zisapel and Laudon, Eur. J. Pharmacol. 136, 259-60, 1987; Laudon et al, J. Endocrinology 116, 43-53, 1988).
It has never been suggested in the scientific literature that melatonin receptors are present in the prostate. Moreover, neither the scientific literature on the subject of melatonin, nor any of the above-mentioned Patents or published Patent Applications disclose or suggest the possibility of utilizing melatonin for treating BPH in humans.